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Biomedical subjects

J H Wolfe

Publications and source records attributed to J H Wolfe.

At least 73 records · Page 4Linked to original sources
PubMed1997

Gene therapy for murine mucopolysaccharidosis type VII.

Mucopolysaccharidosis type VII (MPS VII) is caused by a deficiency in the lysosomal enzyme beta-glucuronidase resulting in the accumulation of undegraded glycosaminoglycans in many tissues. A murine model of MPS VII shares many of the clinical, biochemical and histopathological features of human MPS VII and has provided an opportunity to study novel therapeutic approaches in a system with a uniform genetic background. Retroviral mediated gene therapy directed to the hematopoietic system or to artificial neo-organs resulted in low levels of enzyme in several tissues and reduced lysosomal storage in the liver and spleen. Partial correction of the disease in the eye was observed following an intravitreal injection of recombinant adenovirus. Neither retroviral nor adenoviral mediated gene transfer techniques resulted in a systemic reduction of lysosomal storage. Here we discuss several novel gene transfer approaches designed to increase the systemic levels of beta-glucuronidase in the MPS VII mouse.

Adenoviridae↗
PubMed1997

Critical and subcritical ischaemia.

OBJECTIVES: To stratify leg ischaemia into high and low risk groups with respect to outcome. METHODS: An evaluation of 20 recent publications, reporting the results of 6118 patients with critical ischaemia. Low and high risk patient groups are identified by the definition of critical ischaemia. These groups are analysed with respect to outcome of the patient and limb. MAIN OUTCOME MEASURES: Major amputation and mortality. RESULTS: From these data subcritical (rest pain and/or ankle pressure > 40 mmHg, n = 4089) and critical (tissue loss and/or ankle pressure < 40 mmHg, n = 2029) risk group of patients was identified. The 1, 3 and 5-year mortality is 26%, 44% and 56% with or without reconstruction. For patients in the low risk group, 27% did not lose their leg within the year if treated conservatively. For patients in the high risk group, amputation was required by 95% if treated conservatively, compared to 25% if treated with arterial reconstruction. CONCLUSION: Reconstructive surgery should be viewed from the following, more realistic, perspective. For patients with rest pain (and/or ankle pressure > 40 mmHg), 100% cumulative patency is equivalent to 64% resolution of symptoms at 1 year, as the rest may have improved without treatment. For high risk patients (tissue loss and/or ankle pressure < 40 mmHg), 100% cumulative patency is equivalent to 93% limb salvage at 1 year. Future reports should identify these two groups separately, as the dominant difference between outcome studies is the proportion of subcritical patients in the study rather than better surgical or radiological techniques. This stratification also has an important bearing on pharmacotherapy trials.

Amputation, Surgical↗
PubMed1997

Clostridium difficile colitis after aortic surgery.

OBJECTIVE: To determine the incidence and outcome of Clostridium difficile colitis (CDC) following aortic surgery. DESIGN: Retrospective clinical study, and case-note review. PATIENTS: Of 180 patients undergoing aortic surgery for either aneurysmal or occlusive disease between 1 September 1994 and 31 August 1996 (24 months), 15 (8.4%) developed CDC. There were 12 male and three female patients of median age 65 (range 46-84). RESULTS: Two patients died from multiple organ failure in association with CDC, one of whom underwent negative relaparotomy for suspected ischaemic bowel because the diagnosis of CDC had not been entertained. Previously identified risk factors for CDC comprised: age > 65 (eight); renal impairment (four); chronic obstructive airways disease (seven); coexistent malignancy (three); admission from another hospital (four); H2 antagonist therapy (13); ITU (nine); and/or HDU care (14). Diarrhoea commenced a median of 9 (range 5-26) days, and CDC, was diagnosed a median of 14 (range 10-26) days after operation. All patients received intravenous Cefuroxime, originally prescribed as prophylaxis, for a median of 6 (range 3-16) days prior to onset of CDC. Two patients received 1 additional antibiotic; one received 2; two received 3; and one received 4 prior to onset of CDC. CONCLUSIONS: CDC is a common and potentially serious complication of vascular, and in particular, aortic surgery. Although such patients often possess several risk factors for CDC, colitis frequently follows prolonged 'prophylactic' cephalosporin administration, which should therefore be avoided.

Aged↗
PubMed1997

Myointimal hyperplasia in vein collars for ePTFE grafts.

OBJECTIVE: To understand the cause of intermediate ePTFE graft failure when a venous boot is used. This might give insight into the improvement in patency that results from the use of a venous boot. DESIGN: A histological and radiological study of failed and failing grafts. METHODS: A review of patients operated upon in St Mary's Hospital under the care of a single consultant. RESULTS: Four anastomoses were retrieved following irretrievable occlusion and found to have myointimal hyperplasia at the function between the ePTFE graft and collar. The artery was relatively spared. In a further six patients these results have been corroborated by angiography. CONCLUSIONS: Myointimal hyperplasia occurs at the interface between ePTFE and vein collar and the recipient artery is relatively spared. This manipulation of the site of myointimal hyperplasia may result in improved patency rates.

Angiography, Digital Subtraction↗
PubMed1997

Decreased lysosomal storage in the adult MPS VII mouse brain in the vicinity of grafts of retroviral vector-corrected fibroblasts secreting high levels of beta-glucuronidase.

A deficiency of beta-glucuronidase (GUSB) causes the multisystem progressive degenerative syndrome, mucopolysaccharidosis (MPS) type VII (Sly disease), which includes mental retardation. Animal homologues of MPS VII (ref. 3, 4) are models for testing somatic gene transfer approaches to treat the central nervous system in this and other lysosomal storage disorders. Previous attempts to correct murine MPS VII by gene therapy have successfully treated lesions in some organs but not in the brain. Other experimental modalities have forestalled some disease progression in the brain, but only if done at birth, before the onset of severe lesions, when the animals are phenotypically normal. We tested whether therapeutic amounts of GUSB could be delivered to the diseased adult brain by transplanting cells engineered to super-secrete the normal enzyme for export to surrounding neural tissues. Lysosomal distention was cleared from neurons and glial cells in the vicinity of the grafts, showing that the secreted enzyme could reach the diseased cells and reverse lesions in the severely diseased brain. The ability to correct established lesions will be important for the treatment of many lysosomal storage diseases affecting the brain, because most patients are not diagnosed until lesions are advanced enough to affect phenotype or developmental milestones in early childhood, and some forms of the diseases do not become apparent until later in life.

Animals↗
PubMed1997

Amphotropic and ecotropic retroviral vector viruses transduce midgestational murine fetal liver cells in a dual-chambered cocultivation system.

A beta-glucuronidase cDNA was transferred into fetal liver cells (FLC) from mice affected with mucopolysaccharidosis (MPS) type VII and normal littermates using a retrovirus vector. The cells were transduced by direct cocultivation or by culturing the FLC and vector packaging cells separated by a 0.45 micron filter in a dual-chambered cocultivation system. Gene transduction occurred using an ecotropic or amphotropic vector in FLC obtained from 13.5- and 15.5-day-old murine fetuses. Histochemical staining assays and measurement of enzyme activity demonstrated gene expression in the midgestational FLC. Enzyme secreted into the supernatant from transduced FLC obtained from 13.5-day-old affected fetuses surpassed secreted enzyme from normal, age-matched untransduced FLC. The 13.5 day FLC, transduced by direct cocultivation or by using the dual-chambered system, were transplanted in utero into 13.5-day-old murine fetuses. Proviral sequences were detected in various organs shortly after birth. The results indicate that midgestational FLC can be transduced with an amphotropic vector virus in a dual-chambered cocultivation system without contaminating virus-producing packaging cells and that the transduced cells survive in utero transplantation.

Animals↗
PubMed1997

Glycosaminoglycan storage in cultured neonatal murine mucopolysaccharidosis type VII neuroglial cells and correction by beta-glucuronidase gene transfer.

The inherited deficiency of beta-glucuronidase activity causes the lysosomal storage disorder mucopolysaccharidosis (MPS) type VII (Sly disease). The sequential catabolism of glycosaminoglycans in lysosomes is blocked, and undegraded substrates accumulate in cells of many tissues, including neurons and glia in the brain. To evaluate the deficient metabolic pathway, primary cultures of mixed brain cells were established from newborn MPS VII mice. beta-Glucuronidase levels and glycosaminoglycan accumulation were studied in normal, carrier, and MPS VII cells. Retroviral vector-mediated transfer of a normal beta-glucuronidase cDNA corrected the enzymatic deficiency in MPS VII cells and restored glycosaminoglycan catabolism to normal. High levels of beta-glucuronidase expression were sustained in vector-corrected nondividing glial cell cultures for >2 months. These studies provide an in vitro model for evaluating somatic gene transfer in neural cells affected in mucopolysaccharidoses.

Animals↗
PubMed1997

Endotoxin related early neutrophil activation is associated with outcome after thoracoabdominal aortic aneurysm repair.

BACKGROUND: Thoracoabdominal aortic aneurysm (TAAA) repair is associated with high mortality rates, especially in patients who develop postoperative renal and pulmonary impairment. Organ damage during TAAA repair may be mediated by activated polymorphonuclear neutrophils (PMNs) during a systemic inflammatory response. The association between intraoperative neutrophil activation and postoperative outcome was studied after TAAA surgery. METHODS: Perioperative PMN activation (surface CD11b expression by flow cytometry), plasma endotoxin, plasma endotoxin core antibody, tumour necrosis factor (TNF), and interleukin 1 (IL-1) levels were measured in 21 patients undergoing TAAA repair. RESULTS: Intraoperative PMN CD11b expression was significantly greater in the 11 patients who developed pulmonary and renal complications than in those who made an uneventful recovery (P = 0.0009). In addition, CD11b expression during visceral reperfusion was preceded by a rise in plasma endotoxin level and a fall in antibody level (reflecting binding by absorbed endotoxin) which was significantly greater in patients who developed complications (P = 0.031 and P = 0.001 respectively). Plasma endotoxin level correlated with CD11b expression (r = 0.828, P = 0.001). There were no significant differences in intraoperative plasma levels of TNF and IL-1, or aortic cross-clamp times and blood transfusion volumes between the complicated and uncomplicated repairs. CONCLUSION: Intraoperative neutrophil activation is a marker for the development of postoperative complications after TAAA reconstruction and is associated with endotoxin absorption.

Acute-Phase Reaction↗
PubMed1996

Molecular basis of canine muscle type phosphofructokinase deficiency.

Muscle type phosphofructokinase (M-PFK) deficiency is a rare inherited glycogen storage disease in humans that causes exertional myopathy and hemolysis. The molecular basis of canine M-PFK deficiency, the only naturally occurring animal homologue, was investigated. Lack of M-PFK enzyme activity was caused by a nonsense mutation in the penultimate exon of the M-PFK gene, leading to rapid degradation of a truncated (40 amino acids) and therefore unstable M-PFK protein. A polymerase chain reaction-based test was devised to identify M-PFK-deficient and carrier animals. This represents one of only a few inborn errors of metabolism where the molecular defect has been identified in a large animal model which can now be used to develop and assess novel therapeutic strategies.

Animals↗
PubMed1996

A cDNA encoding canine muscle-type phosphofructokinase.

The canine muscle-type-phosphofructokinase-encoding gene (M-PFK) was sequenced by using a combination of cDNA cloning and RT-PCR amplification. The canine M-PFK sequence shares 88 and 90% identity with rabbit and human M-PFK, respectively. The canine ORF was determined to be 6-bp longer than either human or rabbit M-PFK due to a 6-bp insertion at the end of exon 13.

Amino Acid Sequence↗
PubMed1996

Aortic prosthetic infection: 50 patients treated by radical or local surgery.

Fifty patients with aortic prosthetic infection were managed in a period of 10 years from 1983 to 1993. Twenty-five patients had recurrent sepsis after local surgery (group 1) and 22 of these eventually required radical surgery. Twenty-five patients had radical graft excision as the first procedure (group 2). Group 1 contained an excess of patients with local groin symptoms (11 in group 1 versus five in group 2, P = 0.03) and in this group fewer radiological techniques were used to document the extent of graft infection. The perioperative mortality rate was similar in both groups (seven in group 1 versus five in group 2). The number of amputations was also similar (five in group 1 versus four in group 2). The triad of occlusive disease, aortobifemoral bypass and groin symptoms was associated with eight of nine amputations. While the authors would consider using local techniques if the anastomosis was intact, the graft remained patent and infection appeared to be confined to the groin, this combination is uncommon and radical graft excision remains the preferred treatment.

Amputation, Surgical↗
PubMed1996

Lymphedema.

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Drainage↗
PubMed1996

Smoking and plasma fibrinogen, lipoprotein (a) and serotonin are markers for postoperative infrainguinal graft stenosis.

OBJECTIVES: A number of systemic variables are associated with infrainguinal graft failure and also with experimental smooth muscle hyperplasia. Stenosis is the most common cause of infrainguinal graft thrombosis but it is not known if systemic variables are associated with stenosis. DESIGN, MATERIALS, AND METHODS: In this study, clinical and serological factors were measured and correlated with stenosis development in 81 infrainguinal bypass grafts (52 vein, 29 PTFE; 28 with stenosis) in prospective (n=46) and retrospective (n=35) groups. Pre-existing stenosis was excluded by perioperative graft assessment. RESULTS: There was a significantly greater proportion of smokers in the patients who developed stenosis (11/18; 61%) compared with those who did not (6/28; 21%, p=0.006; chi 2). Patients who developed stenosis also had significantly (Mann Whitney U-tests), higher circulating levels of [median (interquartile range)] fibrinogen (412.5 (356-484.5) vs. 339 (300-397.7) mg/100ml, p=0.003), Lipoprotein (a) (0.20 (0.05-0.45) vs. 0.085 (0.05-0.23) g/l, p=0.03) and 5-hydroxytryptamine (14.1 (6.6-45) vs. 4.41 (3-8.39) nmol/l, p=0.005), than those without stenosis. By logistic regression, these associations were independent of graft material and whether grafts were studied prospectively or retrospectively. CONCLUSIONS: Smoking and plasma fibrinogen, Lp(a) and 5-hydroxytryptamine are markers for postoperative infrainguinal graft stenosis.

Blood Vessel Prosthesis↗
PubMed1996

Central nervous system cell transplantation: a novel therapy for storage diseases?

Many methods of gene transfer to the brain are under study. One employs a neural stem cell based strategy. Transplanting neural progenitor cells that intrinsically secrete missing or therapeutic gene products, or are genetically engineered ex vivo to do so, may provide a strategy for long-term treatment of central nervous system manifestations of a number of neurogenetic diseases. Multipotent neural progenitors or stem cells (or cells that mimic their behavior) are capable of differentiating along multiple central nervous system cell-type lineages. They can engraft as integral members of normal structures throughout the host central nervous system without disturbing other neurobiological processes. They can also be easily genetically manipulated ex vivo. By exploiting their basic biological properties, these cells may be able to deliver therapeutic gene products in a sustained, direct, and perhaps regulated fashion throughout the central nervous system. Furthermore, although they may disseminate these gene products throughout the brain, they nevertheless restrict that distribution to only the central nervous system. Thus, these vehicles may overcome many of the limitations of viral and non-neural cellular vectors, as well as pharmacologic and genetic interventions. The feasibility of this neural stem cell-based strategy has been demonstrated by correcting the widespread central nervous system pathology of a murine model of a prototypical inherited neurodegenerative disease, mucopolysaccharidosis type VII. These studies have helped to establish the use of such cells as a paradigm for transferring other molecules of therapeutic or developmental interest throughout the central nervous system at many ages.

Animals↗